Diuretic composition and method

ABSTRACT

THE INVENTION RELATES TO DIURETIC AND SALURETIC PREPARATIONS IN DOSAGE UNIT FORM, CONTAINING THE HITHERTO UNKNOWN 4-BENZYL-3-N-BUTYLAMINO-5-SULFAMYLBENZOIC ACID OR A SALT THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE BASE AS THE ACTIVE COMPONENT, IF DESIRED TOGETHER WITH A HYPOTENSOR, THE DOSE OF THE DIURETIC BEING BETWEEN 0.2 AND 20 MG., CALCULATED AS THE FREE ACID.

United States Patent 3,793,459 DIURETIC COMPOSITION AND METHOD PeterWerner Feit, Gentofte, and Ole Bent Tvaermose Nielsen, Vanlose, Denmark,assignors to Lovens Kemiske Fabrik Produktionsaktieselskab, Ballerup,Denmark No Drawing. Filed June 16, 1971, Ser. No. 153,880 Claimspriority, application Great Britain, June 8, 1970, 29,792/ 70 Int. Cl.H61k 27/00 US. Cl. 424-319 Claims ABSTRACT OF THE DISCLOSURE Theinvention relates to diuretic and saluretic preparations in dosage unitform, containing the hitherto unknown4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid or a salt thereof with apharmaceutically acceptable base as the active component, if desiredtogether with a hypotensor, the dose of the diuretic being between 0.2and mg, calculated as the free acid.

The invention further relates to a method of treating patients sufferingfrom edematous conditions and hypertension with the dosage units inquestion, administering from 0.2 to 50 mg. daily of the diuretic to thepatient.

The present invention relates to a pharmaceutical composition for thetreatment of edematous conditions and hypertension, to dosage units ofthe composition, and to methods for the treatment of edematousconditions and hypertension.

More particularly, the invention relates to a pharmaceutical compositioncontaining as an active agent at least one member of the group selectedfrom 4-benzyl- 3-n-butylamino-5-sulfamylbenzoic acid and its salts withpharmaceutically acceptable inorganic and organic bases, together withauxiliary agents, and to a dosage unit of the composition for thetreatment of edematous conditions and hypertension.

The substance 4-benzyl-3 n butylamino-S-sulfamylbenzoic acid is a newcompound which may be prepared, for example, by3-amino-4-benzyl-5-sulfamylbenzoic acid being butylated at the N-atom inthe 3-position, as hereinafter described.

4 benzyl 3 nbutylamino 5 sulfamyl-benzoic acid possesses a favourablediuretic and saluretic activity. As far as the saluretic effect isconcerned, the compound causes, in particular, an excretion of sodiumand of chlorine in approximately equivalent proportions, while theexcretion of the potassium ion remains substantially normal, or is onlyslightly increased.

It has been found that among a series of 4-substituted3-R-amino-S-sulfamylbenzoic acids, in which -R represents alkyl,aralkyl, or a hetero radical, the 4-benzyl-3-n-butylamino-4-phenoxy 5sulfamylbenzoic acid has advantageous properties with a view to clinicaluse.

From a pharmaceutical point of view, it is a further advantage that4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid is chemically stableunder acid conditions. Thus, for instance, no discoloration or loss inactivity has been observed in pharmaceutical preparations containing thefree acid, which when given orally is readily resorbed through the upperpart of the gastro-intestinal tract and distributed in the body.

Specifically, it is advantageous that4benzy1-3-n-'butylamino-S-sulfamylbenzoic acid has proved to beoutstanding in having a diuretic effect which is comparable in type andactivity to that of the well known diuretic Furosemide, belonging to thegroup of chlorosulfamylanthranilic acids.

The advantageous diuretic and saluretic effects of 4- ice TABLE IDiuretic activity of OT 1441 in dogs Water Na K 01-, ml./kg. mvaL/kg.mvaL/kg. mvaL/kg.

Dose, ig/kg. 3h 6h 311 611 3h 611 3b 6h Controls 2 It is apparent fromthe Table I that the diuretic effect is very intensive andshort-lasting. It will further be seen that in most instances the effectof a given dose was more pronounced after oral than after intravenousapplication. This may be explained by the renal excretion of the drugbeing so rapid that not enough solute is available to be excreted withinthe short period of rather high serum concentrations after theintravenous injection. -It shows further that the compound isexcellently absorbed from the gastrointestinal tract.

In the animal experiment above the effect of OT 1441 was tested againstthe effect of the well-known diuretic Furosemide which until now hasbeen considered one of the most active diuretics of this type. Thecomparison showed that 4-benzyl-3-n-butylamino-S-sulfamylbenzoic acidwas approximately 30 times as potent as Furosemide on a Weight basis.The maximal effect obtainable with both compounds, however, seemed to bethe same.

As far as the potassium excretion is concerned, Table I aboveillustrates a favorably low kaliuresis when compared to the very highexcretion of water and of sodium.

In order to determine the acute toxicity of 4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid, animal experiments were performed.After intravenous injection an acute LD of 186 mg./kg. (172-201) wasdetermined. This corresponds well to the value of 308 mg./kg. given forFurosemide by Muschaweck and Hajdu (Arzneimittel- EForsch. 14, 44,1964). Thus, the higher diuretic and saluretic activities of 4benzyl-3-n-butylamino-5-sulfamylbenzoic acid taken into account, itstoxicity must be considered extremely low.

When given orally in the above test, doses up to 1 g./ kg. were givenand survived by all mice.

Accordingly, it is the object of the invention to provide apharmaceutical composition with diuretic and saluretic effect which isuseful in the treatment of edematous conditions, e.g. cardiac, hepatic,renal, lung, and brain edema, of edematous conditions during pregnancy,and of other pathological conditions disturbing the balance of theelectrolyte concentration in the body, for example in the form of anabnormal retension of the sodium ion, in the treatment of congestiveheart failure, and in the treatment of hypertension.

With this object in view the compositions of the invention contain as anactive component at least one member of the group consisting of4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid and its pharmaceuticallyacceptable salts with inorganic and organic bases, together with solidor liquid pharmaceutical carriers and auxiliary agents.

In the said compositions, the percentage of the diuretically activesubstance can vary between 0.02 and 20%.

The compositions in question can be worked up to pharmaceutical forms ofpresentation, such as capsules, tablets, pills, dnagees, andsuppositories, or they can be filled into the usual containers forinjectable medicines, such a vials or ampuls or, as far as liquidmixtures for oral use are concerned, they may be filled into bottles andsimilar containers.

Pharmaceutical organic or inorganic, solid or liquid carriers suitablefor enteral and parenteral administration can be used to make up thecompositions. For example, water, gelatine, lactose, starch, magnesiumstearate, stearic acid, talc, vegetable and animal oils and fats, wax,benzyl alcohol, gum, polyalkylene glycol, cetylalcohol, petroleum jelly,cocoa butter, lanolin, and other known carriers for medicaments are allsuitable as carriers here, while stabilizing agents, wetting oremulsifying agents, salts for varying the osmotic pressure, and bufiersfor securing an adequate pH-value of the composition, can be used asauxiliary agents.

Among suitable salts of 4-benzyl-3-n-butylamino-5-sulfamylbenzoic acidfor use in the present compositions mention may be made of the alkalimetal salts, the alkaline-earth metal salts, the ammonium salt, andsalts with organic bases, such as the ethanolamine salt and thediethanolamine salt. Besides, the free acid itself may also be used in acomposition according to the invention.

Thus, for preparations in the form of tablets or the like, or ininjectable preparations, the sodium salt or the potassium salt may beused, being sufficiently water-soluble. For injectable preparations,however, salts with certain organic bases may advantageously be employeddue to their high solubility in water.

The free acid or its salts may also be administered in capsules, or inelfervescent tablets in order to obtain a quick resorption, or insustained-release tablets in order to obtain a prolonged effect which,in particular, is desirable in the treatment of hypertension.

In addition to 4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid or a saltthereof, the compositions of the invention may contain other suitableactive components in the treatment of hypertension and edematousconditions, such as hypotensors, as hydralazine, methyldopa, reserpine,and other Rauwolfia serpentina alkaloids, veratrum a1- kaloids and/ ortranquilizers, such as meprobamate, or ptassiu-m-sparing substances,such as triamterene.

Since hypopotassemia may sometimes occur in the course of prolongedtreatment of hypertensive individuals, it has been found desirable insome cases to include a small amount of an organic potassium salt in thecompositions of this invention, such as potassium acetate, potassiumpropionate, potassium lactate, potassium ascorbate, potassium mandelate,potassium hippurate, or potassium gluconate, or a nontoxic inorganicpotassium salt, such as potassium chloride. Since hypochloremia as wellas hypopotassemia sometimes occurs during treatment of hypertensiveindividuals, potassium chloride may be used to supply chloride ions aswell as potassium ions.

The term veratrum alkaloids, when used in this specification, isintended to cover the group of chemically related organic nitrogenousbases obtained from liliaceous plants belonging to the suborderMelanth-aceae.

The veratrum alkaloids are useful in pure, crystalline form or in theform of mixtures obtained from the powdered root or rhizome. Thepreferred veratrum alkaloids for use in the composition of the presentinvention are veratrum viride, and protovctatrine A and B.

The term rauwolfia alkaloids comprises the group of organic nitrogenousbases which may be obtained from Rauwolfia serpentina Benth. Thiscomponent of the pres-.

ent invention may be used in the form of the powdered whole root or inthe form of the pure crystalline alkaloids, reserpine, rescinamine, anddeserpidine, which are obtainable from the whole root. The aboveexamples of additional active ingredients are not to be consideredlimitative for the compositions of the present invention.

Owing to the short-lasting eifect of4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid, even when administeredorally in the form of capsules, the compound is preferably administeredin the form of sustained-release tablets. In such tablets4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid, pheferably in the formof a water-soluble salt, can be embedded in a tablet core consisting ofa hydrophobic material, such as a wax with a melting point at orslightly above the body temperature. On administration, the compoundwill then gradually be extracted into the gastro-intestinal tractwithout disintegration of the tablet core whereby a controlled diuresisand a prolonged effect is obtained.

In this embodiment, if the composition of the invention in dosage unitform contains other active ingredients, these may be contained in thecoating material for the core of the sustained-release tablet 'whereby atablet is provided which is particularly advantageous in the control ofhypertension.

Thus, the coating may contain ingredients such as reserpine and otheralkaloids, methyldopa, and similar hypotensors.

On the other hand, the sustained-release tablet may advantageouslycontain a potassium salt in the tablet core in order to obtain a slowrelease of the potassium ion, thereby avoiding disturbances in thegastrointestinal tract due to instantaneous high salt-concentrationsafter the intake.

Another object of the invention resides in the selection of a dose ofthe 4-benzyl-3-n-buty1amino-S-sulfamylbenzoic acid and its salts whichcan be administered so that the desired activity is achieved withoutsimultaneous secondary effect. It has been found that4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid and its salts areconveniently administered in dosage units containing not less than 0.2mg., and up to 20 mg., preferably from 0.5-5 mg, calculated as the freeacid 4-benzyl-3-n-buty1-amino- S-sulfamylbenzoic acid.

By the term dosage unit is meant a unitary, i.e. a single dose which iscapable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically stable unit dosecomprising either the active material as such or a mixture of it withsolid or liquid pharmaceutical diluents or carriers.

If the composition is to be injected, a sealed ampoule, a vial or asimilar container may be provided containing a parenterally acceptableaqueous or oily injectable solution or dispersion of the active materialas the dosage unit.

It is still another object of the invention to provide a method oftreating patients suffering from edematous conditions and hypertension,the method comprising administering to the patient from 0.2 to 25 mg.per day of 4- benzyl-3-n-butylamino-S-sulfamylbenzoic acid or acorresponding dose of one of its salts with pharmaceutically acceptablebases. Preferably, the compound is given in the form of the dosage unitaforesaid.

For oral administration, the dosage unit may conveniently contain from0.2-10 mg. of the 4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid, assuch or in the form of one of its salts, the unit being in the form of atablet, a pill, or a capsule, to be given at suitable intervals, forinstance once, twice, or thrice daily, always depending, however, on thepatient and his condition. Preferably, each tablet contains from 0.5 to5 mg. of the 4-benzyl-3-nbutylamino-S-sulfamylbenzoic acid, or acorresponding amount of one of its salts. If the dosage unit isinjectable, the unit may consist of from 0.1 to 5 mg. of the 4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid, and conveniently from 0.2. to 2mg. dissolved in an aqueous solvent, the said dosage unit for instancebeing enclosed in an ampul containing, for example, 2 ml. of a 0.025percent aqueous solution of the sodium salt of4-benzyl-3-n-butylamino-5- sulfamylbenzoic acid.

The parenteral preparations are in particular useful in the treatment ofconditions in which a quick dehydration is desirable, e.g. in theintensive therapy in the case of edemas in the lung. In the continuoustherapy of the patients suffering from e.g. hypertension, the tablets01' capsules may be the appropriate form of pharmaceutical preparationowing to the prolonged effect obtained when the drug is given orally, inparticular in the form of sustained-release tablets.

In the treatment of heart failure and hypertension such tablets mayadvantageously contain other active components, as specifiedhereinbefore.

Thus, for instance, the tablets may contain each 0.5 mg. of the 4benzyl-3-n-butylamino-S-sulfamylbenzoic acid or one of its salts incombination with hydralazine in amounts from to 50 mg, or reserpine inamounts from 0.05 to 0.5 mg., or from 20 to 100 mg. in the form ofpowdered whole root, or protoveratrine in amounts ranging from 0.05 to0.4 mg, and if in the form of a mixture of alkaloids, e.g. Veratrumviride, 50 mg. is preferred, or methyldopa in amounts from 100 to 500mg., and furthermore the tablets may contain, as a tranquilizer,meprobamate [2:2-di(carbamoyloxymethyl)-pentane] in amounts from 100 to400 mg, preferably 150 mg. to 250 mg.

A method of producing 4 benzyl-3-n-butylamino-5- sulfamylbenzoic acidand salts thereof will be described in details in the following.

4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid A. Ethyl4-benzoyl-3,5-dinitrobenzoate.--A mixture of4-carbethoxy-2,6-dinitrobenzoic acid (85 g.), thionylchloride (85 ml.)and pyridine (0.25 ml.) is refluxed for about 3 hours. The resultingsolution is evaporated in vacuo and the remaining4-carbethoxy-2,6-dinitrobenzoyl chloride is dissolved in dry benzene(130 ml.). Anhydrous aluminum chloride (50 g.) is then added in portionsto the refluxing solution while stirring vigorously. After the additionis completed, the mixture is stirred and refluxed for a further 2 hours.After cooling to about 50 C., methylene chloride (250 ml.) is addedfollowed by a mixture of ice (250 g.) and concentrated hydrochloric acid(150 ml.). After additional stirring for about 1 hour, the organic layeris separated, washed with water and evaporated in vacuo. The residue istriturated with hot ethanol (200 ml.) and, after cooling, the resultingprecipitate is collected by filtration, and washed with cold ethanolfollowed by petroleum ether. After drying and recrystallization frommethylcellosolve, ethyl 4-benzoyl-3,5-dinitrobenzoate is obtained with amelting point of 172-173 C.

B. 4-benzoyl 3,5 dinitrobenzoic acid.To a stirred suspension of ethyl4-benzoyl-3,S-dinitrobenzoate (160 g.) in ethanol (800 ml.), 2 N sodiumhydroxide (260 ml.) is added dropwise within minutes. After additionalstirring for 10 minutes, the resulting solution is clarified byfiltration and is then acidified by the addition of 4 N hydrochloricacid (150 ml.). After cooling, the resulting precipitate is collected byfiltration and washed with water. After drying and recrystallizationfrom aqueous ethanol, 4-benzoyl 3,5 dinitrobenzoic acid is obtained witha melting point of 248-251" C. (dec.).

C. S-amino 4 benzoyl 3 nitrobenpoic acid.A mixture of 4-benzoyl 3,5dinitrobenzoic acid (110 g.) and pyridine (220 ml.) is heated on a steambath for about 15 minutes to afford the formation of thepyridinium-salt. Water (440 ml.) is then added and the mixture is cooledto -22 C. To the stirred mixture,

sodium dithionite (124 g.) is then added in portions during 7-8 minuteskeeping the temperature at 20-22 C. After the addition is completed thestirring is continued for a further 6-7 minutes allowing the temperatureto drop to 12-15 C. The resulting red solution is carefully acidifiedwith concentrated hydrochloric acid (380 ml.) keeping the temperaturebelow 22 C. The reaction mixture is left at room temperature for about20 hours. The precipitated material is then collected by filtration andwashed with water. After recrystallization from acetonitrile, S-amino 4benzoyl 3 nitro-benzoic acid is obtained with a melting point of 203-204C. (dec.).

D. 4-benzoyl 3 nitro 5 sulfamylbenzoic acid.A mixture of S-amino 4benzoyl 3 e nitrobenzoic acid (28.6 g.) and concentrated hydrochloricacid (100 ml.) is heated on a steam bath for about 10 minutes and thencooled. The amine is diazotized by dropwise addition of a solution ofsodium nitrite (7.6 g.) in water (40 ml.) while stirring at 0-5 C. Theresulting diazonium-mixture is poured into a solution of cupric chloridedihydrate (4.0 g.) in water (15.0 ml.) and acetic acid (140 ml.)saturated with S0 while stirring at room temperature. The stirring iscontinued for a further 1 hour and the mixture is then diluted with coldWater (300 ml.). The precipitated 4-benzoyl-5-chlorosulfonyl 3nitro-benzoic acid is collected by filtration and washed with water. Thedamp filter-cake is then added in portions to concentrated ammoniumhydroxide (300 ml.) While stirring at 10-12 C. After additional stirringat room temperature for about 20 hours, the solution is carefullyacidified to pH=2.0 with concentrated hydrochloric acid. The resultingprecipitate is collected by filtration and washed with water. Afterdrying and recrystallization from aqueous ethanol,4-benzoyl-3-nitro-5-sulfamylbenzoic acid is obtained with a meltingpoint of 234-235 C.

E. 4-amino 6 carboxy 3 phenyl 1,2 benzisothiazole-1,1-dioxide.To astirred solution of 4-benzoyl- 3-nitro-5-sulfamylbenzoic acid (7.0 g.)in a mixture of pyridine (15 ml.) and water (50 ml.), sodium dithionite(14 g.) is added in portions. The mixture is heated on a steam bath forabout 1 hour and is then evaporated in vacuo. The remaining material isdissolved in hot water (about 50 ml.) and the solution is acidified withconcentrated hydrochloric acid (15 ml.). The mixture is heated on asteam bath for 15 minutes and left at room temperature for about 20hours. The resulting precipitate is collected by filtration and washedwith water. After drying and recrystallization from a mixture ofacetonitrile and methylcellosolve, 4-amino-6-carboxy-3-phenyl-1,2-benzisothiazole 1,1 dioxide is obtained with a melting point of287-288 C. (dec.).

F. 3-amino 4 benzyl 5 sulfamylbenzoic acid.A mixture of4-amino-6-carboxy 3 phenyl 1,2 benzisothiazole-1,1-dioxide (3.0 g.),aqueous hydrazine hydrate (6.0 ml.), potassium hydroxide (2.0 g.), water(4.0 ml.) and diethylene glycol (25 ml.) is stirred at 130140 C. for 3hours. The temperature is then slowly raised to 215 C. allowing volatilematerial to distil off. The stirring at 215 C. is continued for afurther 3 hours. After cooling and dilution with water (20 ml.), thereaction mixture is acidified with concentrated hydrochloric acid (5ml.). The resulting precipitate is collected by filtration and washedwith water. After drying, and recrystallization from ethanol 2 amino 4benzyl-5- sulfamylbenzoic acid is obtained with a melting point of285-286" c. (dec.).

G. Sodium salt of 4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid.To asuspension of 3-amino 4 benzyl- 5-sulfamylbenzoic acid (13.5 g.) inn-butanol (400 ml.), concentrated sulphuric acid (3.0 ml.) is added. Thereaction mixture is then refluxed under such conditions that the waterformed during the reaction is separated. When the NMR-spectrum of asample of the reaction mixture diluted with n-butanol shows that morethan of the n-butyl 3-amino 4 benzyl 5 sulfamylbenzoate intermediateformed is converted into the corresponding 3-nbutylaminobenzoate (whichcauses a frequence shift to higher field of the two doublets of thearomatic protons of the ring carrying the sulfamyl-group) 2 N sodiumhydroxide (100 ml.) is added and the mixture refluxed for a further 30minutes. After this saponification, the reaction mixture is neutralizedto a pH of 8 by the addition of hydrochloric acid. After cooling, theresulting precipitate is filtered off, washed with a minor amount oficecold water and dried. After recrystallization from water, the sodiumsalt of 4-benzyl-3-n-butylamino sulfamylbenzoic acid is obtained as adihydrate with a melting point of 285-290 C. (dec.) after loss of waterof crystallization at about 110 C.

H. 4 benzyl-3-n-butylamino 5 sulfamylbenzoic acid.Sodium 4benzyl-3-n-butylamino 5 sulfamylbenzoate dihydrate (11.0 g.) isdissolved in hot water (110 ml.) and the solution is acidified withacetic acid ml.). The resulting precipitate is, after cooling, collectedby filtration and washed with water. After drying and recrystallizationfrom aqueous ethanol, 4-benzyl-3-nbutylamino-5-sulfamylbenzoic acid isobtained with a melting point of 234-235" C.

The following non-limiting examples are illustrative of The ingredientswere mixed and screened through a mesh per linear inch sieve andsubsequently treated with an aqueous solution of gelatin -(4 percent) insufficient amount to form a granulate. The granulate was dried andbroken on a 16 mesh per linear inch sieve. After addition of talc, thegranulate was compressed into tablets of 180 mg. each, using 8 mm.punches and dies, to obtain 3000 tablets, each containing 2 mg. of thefree 4- benzyl-3-n-butylamino-S-sulfamylbenzoic acid.

EXAMPLE 2 Capsules containing'the free 4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid Ingredients: G.

Micronized 4 benzyl 3 n butylamino-S- sulfamylbenzoic acid 2.25 Lactose184 Magnesium stearate 2 The ingredients were mixed and passed through a60 mesh per linear inch sieve and subsequently further mixed for 15minutes. The mixture was filled into No. 3 gelatin capsules (Parke,Davis and Co.), using a semiautomatic capsule-filling machine shaken byvibrator. Each capsule contains 125 mg. of the mixture, and in all 1500capsules, each containing 1.5 mg. of the free 4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid were obtained.

EXAMPLE 3 Capsules containing 4-benzyl-3-n-butylamino-5- sulfamylbenzoicacid and methyldopa Ingredients: G. 4 benzyl 3 nbutylamino-S-sulfamylbenzoic acid 0.8 Lactose 17 Talc 15 D,L-methyldopa200 The ingredients were mixed and passed through a 60 mesh per linearinch sieve. The resultant mixture was subdivided and filled intocapsules, each containing 0.4 mg. of the freebenzyl-3-n-butylamino-S-sulfamylbenzoic acid and mg. of D,L-methyldopa.

EXAMPLE 4 Ampules containing the sodium salt of4-benzyl-3-nbutylamino-isulfamylbenzoic acid Ingredients:

4 benz'yl 3 n-butylamino-5-su1famylbenzoic acid g Y 2 Sodium hydroxide g0.13 Sodium chloride -g 36 Sterile water up to ml 4000 The acid wassuspended into water, the suspension was adjusted to pH 7.5 with aqueoussodium hydroxide and then diluted up to 4000 ml. The resulting solutionwas sterilized by filtration. The sterile solution was thereafter filledinto ampules under aseptic conditions, yielding 2000 ampules of 2 ml.each.

EXAMPLE 5 Tablets containing '4-benzyl-3-n-butylamino-5- inch sieve.Thereafter the other ingredients were incorporated, and the mixture wasgranulated with sufficient ethyl alcohol/water (60, percent). Thegranulate was dried and broken on a 16 mesh per linear inch sieve. Afteraddition of-200 g. of talc and 20 g. of magnesium stearate, and mixing,the mixture was compressed into tablets, using 10 mm. punches and dies,yielding tablets of 340 mg. containing 0.8 mg. of4-benzyl-3-n-butylamino-5- sulfamylbenzoic acid and 0.1 mg. ofreserpine.

In a similar manner, tablets were prepared which contained 0.8 mg. of4-benzyl- 3-n-butylamino-S-sulfamylbenzoic acid, and 10 mg. ofhydralazine.

EXAMPLE 6 Tablets containing 4-benzyl-3-n-butylamino-5-sulfamylbenzoicacid and potassium chloride The ingredients were thoroughly mixed andwithout granulation converted into tablets using 11 mm. punches anddies, yielding 5000 tablets of 526 mg., each containing '2 mg. of4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid and 500 mg. ofpotassiumchloride.

EXAMPLE 7 Sustained-release tablets containing each 3 mg. of 4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid in the form of its sodiumsalt 2700 g. of lactose and 45 g. of the sodium salt of 4 benzyl3-n-butylamino-S-sulfamylbenzoic acid were granulated with a 10 percentgelation solution, dried and screened through a 60 mesh per linear inchsieve. The granulate was mixed with 290 g. of stearyl alcohol and g. oftalc, and the mixture was converted into tablets using 8 mm. punches anddies resulting in 15,000 tablets each of 210 mg. The tablets were coatedin a tablet coating machine operating on the air suspension principlewith a solution of 70 g. of methylcellulose in 1100 ml. of chloroformand 900 m1. of methanol. On completion of this coating process, thetablets were maintained suspended and circulating in the air streamwhile the temperature was raised to 75 C. and then lowered. Theincreased temperature may be provided by increasing the temperature ofthe air, by radiation, by high frequency heating, or otherwise, wherebythe stearyl alcohol of the tablet core is liquified and after cooling,tablets are provided in which the active material is embedded into amatrix of stearyl alcohol from which it is liberated slowly in thegastro-intestinal tract by diffusion without disintegration of thetablet.

EXAMPLE 8 Sustained-release tablets containing 1.0 mg. of 4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid as its sodium salt, and 0.1 mg. ofreserpine Sustained-release tablets were prepared as described inExample 7, each containing 1.0 mg. of the sodium salt of4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid embedded in a matrix ofstearyl alcohol. In a manner known per se the tablets were coated withsaccharose containing reserpine. The coating was performed in a pan bysuccessively adding an aqueous solution containing 65% saccharose, 0.6%gelatin, and 0.5% reserpine until the coating layer of each tabletcontained 0.1 mg. reserpine.

What we claim is:

1. A diuretic pharmaceutical preparation comprising a member of thegroup consisting of 4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid andsalt with a pharmaceutically acceptable base together with an atoxicpharmaceutically acceptable carrier, the quantity of the said memberbeing between 0.2 and 20 mg., calculated as the free4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid.

2. A pharmaceutical preparation in oral dosage unit for-m according toclaim 1, wherein the active member is 10 the4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid as an alkali metal salt.

3. A pharmaceutical peraparation in oral dosage unit form according toclaim 1, wherein the active member is the free4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid.

4. An injectable pharmaceutical preparation in dosage unit formaccording to claim 1, in which the units contain from 0.4 to 4 mg. of4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid in the form of a saltwith a pharmaceutically acceptable base, dissolved in an aqueous medium.

5. The method for producing diuretic activity in a patient, whichcomprises administering to the patient from 0.2 to 50 mg. per day of amember of the group consisting of4-benzyl-3-n-butylamino-S-sulfamylbenzoic acid, and salt with apharmaceutically acceptable base.

6. A method as claimed in claim 5, which comprises the oraladministration of an alkali metal salt of 4-benzyl-3-n-butylamino-5-sulfamylbenzoic acid in the form of tablets.

7. A method as claimed in claim 5, which comprises the oraladministration of the free 4-benzyl-3-n-butylamino-S-sulfamylbenzoicacid in the form of tablets.

8. A method as claimed in claim 5, which comprises the oraladministration of the free 4-benzyl-3-n-butylamino-5- sulfamylbenzoicacid in the form of capsules.

9. A method as claimed in claim 5, wherein the active member isadministered orally in the form of a sustainedrelease preparation inwhich the dose of 4-benzyl-3-nbutylamino-S-sulfamylbenzoic acid isranging from 0.2 to 20 mg.

10. A method as claimed in claim 5, which comprises injection of anaqueous solution of a salt with a pharmaceutically acceptable base of4-benzyl-3-n-butylamino-5- sulfamylbenzoic acid in doses from 0.2 to 50mg.

References Cited Chemical Abstracts 73 :55831j (1970) JEROME D.GOLDBERG, Primary Examiner

